1. Field of the Invention
This invention is directed to azaanthrapyrazoles, namely to 2-aminoalkyl-5-aminoalkylamino substituted isoquino [8,7,6-cd] indazole-6-(2H)-ones and to 2-aminoalkyl-5-aminoalkylamino substituted-isoquino [5,6,7-cd] indazole-6(2H)-ones. These compounds have been shown to have antitumor activity.
2. Background
Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been reported which show antitumor activity in clinical trials. Of particular interest has been ametantrone, 1,4-bis{[2-(2-hydroxyethylamino) ethyl]amino}anthracene-9,10-dione, and mitoxantrone, 5,8-dihydroxy-1,4-bis{[2-(2-hydroxyethylamino)ethyl]amino}anthracene-9,10- dione. [Zee-Cheng et al., J. Med. Chem. 21, 291-4 (1978); Cheng et al., "Progress in Medicinal Chemistry", Ellis, G. P. and West, G. B., eds.; Elsevier: Amsterdam, 1983, Vol. 20, pp. 83 and references cited therein]. Mitoxantrone is a broad spectrum oncolytic agent, whose activity is similar to that of the anthracycline antibiotic doxorubicin. Clinical trials have demonstrated that mitoxantrone has particularly promising activity in the treatment of advanced breast cancer, acute leukemia and lymphoma [Legha, Drugs of Today, 20, 629 (1984)]. Although animal studies have demonstrated a diminished cardiotoxicity in comparison to doxorubicin, some clinical cardiotoxicity has been observed also with mitoxantrone, mostly in patients previously treated with doxorubicin (R. Stuart Harris et al., Lancet, 219, (1984) and references cited therein). Ametantrone has been reported to be, in animals, about 10-fold less potent and less cardiotoxic than mitoxantrone. Because a delayed toxicity is observed only with mitoxantrone after administration of the two drugs by the i.p. route to non-tumor bearing rats at equieffective antitumor dosages, it is suggested that the presence of the 5, 8-dihydroxy substitution in mitoxantrone might be implicated in the delayed deaths [Corbett et al., Cancer Chemother. Pharmacol., 6, 161, (1981)].
In addition, both mitoxantrone and ametantrone have a remarkable myelodepressive toxicity and both compounds show cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. Such a resistance, which is named multidrug resistance, involves a number of antitumor antibiotics, among which are amacrine and podophyllotoxinic derivatives, and this resistance is one of the main reasons for therapeutical failures in the treatment of solid tumors with such antibiotics.
In an attempt to overcome the above mentioned drawbacks, some chromophore modified anthracenediones have been prepared. For example, E.P. Patent Application 103,381 discloses 2-aminoalkyl-5-aminoalkylamino substituted anthra [1,9-cd] pyrazol-6(2H)-ones (anthrapyrazoles) which are claimed to have antitumor activity. The antitumor activity of said compounds in a number of preclinical models has been reported by H. D. Hollis Showalter et al. [J. Med. Chem., 30, 121-131, (1987)]. However, anthrapyrazoles are not devoid of toxic side effects, with severe leukopenia (W.H.O. grade 3 and 4) and neutropenia (W.H.O. grade 4) being dose limiting in phase I and phase II clinical trials with the anthrapyrazole CI-941 [I. E. Smith et al., J. Clin. Oncol. 9, 2141-2147, (1991)]. Moreover, a marked nephrotoxicity is associated with CI-941 treatment in the rat [D. Campling and M. E. C. Robbins, Nephrotoxicity, Peter H. Dekker Bach editor, pp. 345-352, (1991), New York; see Chemical Abstract 116:294n, (1992)], and these authors suggest that renal injury may be a clinical problem with anthrapyrazole therapy.
Therefore, the search for newer active analogues is still highly desirable.
We have now discovered that the introduction of one nitrogen atom in the position 9 or in the position 8 of the above mentioned anthra [1,9-cd] pyrazol-6(2H)-ones provides 2-aminoalkyl-5-aminoalkylamino substituted isoquino [8,7,6-cd] indazole-6-(2H)-ones and 2-aminoalkyl-5-aminoalkylamino substituted-isoquino [5,6,7-cd] indazole-6(2H)-ones respectively, which are endowed with marked antitumor activity.